The long-range objective is to improve outcome in human cancer by using a new approach called Helical Tomotherapy. Helical Tomotherapy is the integration of intensity modulated radiotherapy with helical computed tomography, and has the ability to provide exquisite conformality, with continuous verification and rapid adaptation. It enables two hypotheses to be tested: (1) Conformal dose escalation will lead to improved local control without increase of epsilon complications and, in selected subsets of patients, to improved survival. We propose to escalate by increasing dose-per-fraction in Phase I trials to identify to appropriate schedules for future for future Phase III testing. (2) Conformal avoidance of normal tissues at risk will reduce the incidence of complications, leading to improved quality of life. This is applicable especially where tumor volumes cannot be determined with certainty although normal tissues at risk can be delineated accurately. Central to the testing of both of these hypotheses is the capability of Tomotherapy to deliver adaptive radiotherapy which accommodates ongoing changes in target geometry and in treatment delivery. In Research Project 1 we shall further develop optimized methods of tomotherapy delivery, including the implementation of adaptive radiotherapy. This allows for a closed circuit loop to correct for previously undetected errors in radiation delivery on an ongoing basis. In Research Projects 2 and 3 we shall perform dose escalation using the capabilities of tomotherapy linked through the commonality of fraction- size escalation. In Project 3 dose escalation will be carried out using fraction-size escalation for prostate cancer based on its slow proliferation as well as on reduced volumes irradiated. In Research Project 4 and 5 we shall test the conformal avoidance strategy in canine nasopharyngeal cancer and human head and neck cancer, using Phase II clinical trial methodology. These projects will be supported by three cores: Administrative Biostatistics and Radiobiology, and Physics, Computers and Dosimetry. This program project represents a unified effort, testing both dose escalation and conformal avoidance, using adaptative tomotherapy capabilities with multiple degrees of synergy between the various projects. When this program project is complete it could have as large an impact on the practice of radiation oncology as the introduction of linear accelerators in the 1960. Our Program Project will allow Tomotherapy to reach a level of scientific and technological maturity where, in the future, technological intercomparisons through Phase III trials may be undertaken.